NOVEL PROCESS FOR THE PREPARATION OF ETRAVIRINE

Description

FIELD OF THE INVENTION:

[0001] The present invention relates to novel method for synthesis of non-nucleoside reverse transcriptase inhibitor 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5 dimethylbenzonitrile (Etravirine)

BACKGROUND OF THE INVENTION:

[0002] ,4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5 dimethylbenzonitrile, Etravirine (I)marketed under the brand name of INTELENCE by Tibotec.

[0003] INTELENCE is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). Reverse transcriptase a viral DNA polymerase enzyme that HIV needs to reproduce. Intelence blocks the enzymatic function of reverse transcriptase and prevents completion of synthesis of the double-stranded viral DNA, thus preventing HIV from multiplying.

[0004] Etravirine and its production method is first reported in US 7037917. This method of synthesizing Etravirine describes treating 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile with NH₃ in presence of 1,4-dioxane in a pressure vessel at 150 °C for 4 days.

[0005] Drugs of the Future 2005, 30(5): 462-468 discloses that 4-guanidinobenzonitrile is cyclized with diethylmalonate by means of sodium ethoxide to give 4-(4,6-dihydroxypyrimidine-2-yl-amino)- benzonitrile, which upon treatment with POCl₃ yields the corresponding dichloro derivative. Further bromination with bromine and sodium bicarbonate in aqueous methanol affords 4-(5-bromo-4,6-dichloropyrimidin,2-ylamine)-benzonitrile, which on condensation with the sodium salt of cyano-2,6-dimethylphenolate in presence of N-methylpyrrolidone and dioxane gives 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile, followed by the aminolysis of the same intermediate yields Etravirine. It also discloses another process in which 5-bromo-2,4,6-trichloropyrimidine is reacted with 4- aminobenzonitrile in presence of diisopropylethylamine gives 4-(5-Bromo-4,6-dichloro-pyrimidin-2-ylamino)-benzonitrile, which is then reacted with 4-hydroxy-3,5-dimethylbenzonitrile to give 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile, followed by the aminolysis of the same intermediate yields Etravirine.

[0006] WO 2010150279 describes a process for Etravirine, comprising condensation of 2,4,6-trichloropyrimidine with 3,5-dimethyl-4-hydroxybenzonitrile gives 4-[(2,6-dichloro)-4-pyrimidinyloxy]-3,5-dimethyl benzonitrile, which is condensed with 4-aminobenzonitrile. Resulting compound on aminolysis followed by halogenation gives Etravirine. WO2006/087387 discloses Etravirine N-oxide and a process for preparing the same. The prior art processes for preparing Etravirine involves aminolysis. The reaction of desired intermediate with ammonia even in refluxing dioxane requires more time for the reaction completion. Therefore, there exists a need in the art for an improved process for the preparation of Etravirine, which is safe and commercially viable.

[0007] The present invention relates to a novel process for the preparation of Etravirine, which is commercially viable, less time cycle comparatively with prior art processes and it also provides novel intermediates which are useful in the preparation of Etravirine.

OBJECT OF THE INVENTION

[0008] The principle object of the present invention is to provide novel method for the synthesis of Etravirine.

[0009] One more object of the present invention is to provide novel intermediates, which are useful for the preparation Etravirine

[0010] Another object of the present invention is to provide Etravirine in high yield and high purity.

SUMMARY OF THE INVENTION

[0011] In one aspect, present invention provides a novel process for the preparation of Etravirine, comprising the steps of:

a) condensing ethyl cyanoacetate with N-cyanophenylguanidine,

b) converting OH- group of the formula (II) into a leaving group of formula (III),

c) protecting amino group of formula (III),

d) brominating compound of formula (IV),

e) condensing formula (V) with 3,5-dimethyl-4-hydroxybenzonitrile, and

f) deprotecting formula (VI) to isolate Etravirine.

[0012] In another aspect, present invention provides novel intermediates of formula (II), (III), (IV), (V) and (VI). Also disclosed is a process for purifying Etravirine comprising:

a) dissolving Etravirine in suitable solvent,

b) removing the solvent,

c) optionally adding water, and

d) isolating pure Etravirine.

[0013] In another aspect, present invention provides Etravirine in high yield and high purity.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention relates to a novel process for the preparation of Etravirine, comprises condensing ethyl cyanoacetate with N-cyanophenylguanidine to obtain -OH compound of formula (II), which is further converted to a leaving group of formula (III). Compound of formula (III) is protected and brominated to yield compound of formula (IV). Condensation of formula (IV) with 3,5-dimethyl-4-hydroxybenzonitrile gives formula (VI), and a deprotection of formula (VI) results into Etravirine.

[0015] The present invention further relates to process for purifying Etravirine. The present invention also provides novel intermediates of Etravirine.

[0016] The main aspect of the present invention is to provide a novel method for the synthesis of Etravirine as shown in scheme I, comprising the steps of:

a) condensing ethyl cyanoacetate with N-cyanophenylguanidine,

b) converting OH- group of the formula (II) into a leaving group of formula (III),

c) protecting amino group of formula (III),

d) brominating compound of formula (IV),

e) condensing formula (V) with 3,5-dimethyl-4-hydroxybenzonitrile, and

f) deprotecting formula (VI) to isolate Etravirine.

[0017] In one embodiment of the present invention, ethylcyano acetate is condensed with N-cyanophenyl guanidine to give 4-(4-Amino-6-hydroxy-pyrimidin-2-ylamino)-benzonitrile of formula (II) in presence of a base in an organic solvent, wherein the base is selected from inorganic base or organic base. The inorganic base is selected from alkali metal alkoxides such as potassium-tert-butoxide, sodium-tert-buoxide, lithium-tert-butoxide preferably potassium tert butoxide; alkaline metal hydroxides such as sodium hydroxide, potassium hydroxide; alkaline metal carbonates such as sodium carbonate, potassiumcarbonate; metal hydrides such sodium hydride. The organic bases such as diethyl amine, triethyl amine, pyridine; The organic solvent is selected from polar protic solvents such as methanol, ethanol, n-propanol, isopropanol, acetic acid, n-butanol, formic acid, preferably n-butanol.

[0018] In another embodiment of the present invention, -OH group of formula (II) is converted to formula (III), wherein L is a suitable leaving group, selected from a suitable leaving group known in the art, preferably chloro, bromo, tosylates, mesylates, more preferably chloro. The conversion of OH-group into leaving group can be carried out by process known in the art. The conversion of OH- into leaving group of the present invention, preferably chloro is carried out by treating compound of formula (II) with chlorinating agent selected from phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, preferably phosphorus oxychloride.

[0019] In another embodiment of the present invention, the amine group of formula (III) is protected with a suitable protecting group by treating with a suitable amino protecting agent in presence of a base and solvent to give formula (IV), wherein the P is a protecting group selected from the amine protecting group such as carbobenzyloxy (Cbz), p-Methoxybenzyl carbonyl, tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl (Bn), Carbamate group, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), Tosyl (Ts) Other Sulfonamides (Nosyl & Nps); preferably benzoyl group. The protection is carried out by treating formula (III) with benzoyl chloride in presence of a base selected from triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO), pyridine or 4-(dimethylamino)pyridine (DMAP), preferably DMAP, and the solvent is selected from polar aprotic solvents such as acetone, tetrahydrofuran, methyl ethyl ketone, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide; preferably acetonitrile. The protection can be carried out by following the procedure, as described in Theodora W. Greene and Peter G. M. Wuts, "Protecting Groups In Organic Synthesis," third edition, John Wiley and Sons, New York. N.Y.

[0020] In another embodiment of the present invention, 4-(4 amino protected -6-leaving group substituted-pyrimidin-2-ylamino)-benzonitrile of formula (IV) is brominated with a brominating agent to give formula (V), wherein the bromination is carried out by treating with a brominating agent such as bromine in presence of an acid such as acetic acid or N-bromosuccinamide, in suitable organic solvent selected from inert solvents such as diethylether, chloroform, dichloromethane, carbon tetrachloride; preferably dichloromethane.

[0021] In another embodiment of the present invention, the brominated compound of formula (V) is condensed with 3,5-dimethyl-4-hydroxybenzonitrile to give formula (VI) in presence of a base in a suitable solvent. The base is selected from triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]-octane (DABCO), pyridine or 4-(dimethylamino)pyridine (DMAP), or combination thereof; most preferably the combination of DBU and DMAP; The organic solvent is selected from polar aprotic solvents such as 1,4-dioxane, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide; preferably N,N-dimethylformamide.

[0022] Yet another embodiment of the present invention, the condensed compound of formula (VI) is deprotected by treating with a base in a suitable solvent or mixtures thereof, wherein the base is selected from the alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, Lithium hydroxide preferably lithium hydroxide; and an organic solvents or mixtures thereof are selected from polar aprotic solvents and polar solvents such as methanol, ethanol, n-propanol, isopropanol, acetic acid, n-butanol, formic acid, such as, acetone, tetrahydrofuran, methyl ethyl ketone, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide; preferably mixture of acetonitirile and IPA. Also described is a process for purifying Etravirine comprising the steps of:

a) dissolving Etravirine in suitable solvent;

b) removing the solvent;

c) optionally adding water; and

d) isolating pure Etravirine.

[0023] In one embodiment the Etravirine is dissolved in suitable solvent, wherein the suitable solvent is selected from water miscible solvent. The water miscible organic solvent is selected from polar solvents such as methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile, acetic acid, dioxane, preferably acetone.

[0024] In another embodiment the solvent is removed from the Etravirine solution to obtain Etravirine solid, preferably 60-90% more preferable 70-80% of solvent is removed from Etravirine solution.

[0025] In one more embodiment , to the obtained Etravirine solid is optionally added water and isolated pure Etravirine.

[0026] The crude Etravirine is purified by treating with water miscible organic solvent, wherein the water miscible organic solvent is selected from polar solvents such as methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile, acetic acid, dioxane, tetrahydrofuran, preferably acetone. From the resulting solution around 70-80% of solvent is distilled off. The obtained solid is optionally treated with water to yield pure Etravirine.

[0027] Another aspect of the present invention is to provide novel intermediates of formula (II), (III), (IV), (V) and (VI) which are useful in the preparation of Etravirine,



wherein, L is a suitable leaving group and P is suitable amino protecting group.

[0028] Certain specific aspects and embodiments are further explained in more detailed with the following examples. These examples should not be construed as limiting the scope of the invention in any manner.

EXAMPLES:

Example 1:

Preparation of 4-(4-Amino-6-hydroxypyrimidin-2-ylamino)benzonitrile (II):

[0029] 2000 ml of n-butanol and 192.8 g of potassium-tert-butoxide were added to the reaction vessel at 45 ± 5 °C and stirred for 30 mins. To the reaction mixture was added 194.42 g of ethylcyano acetate over 15 min and added 250 mL of n-butanol. The reaction mixture was heated to 60 ± 5 °C under stirring and was added 250 g of N-cyanophenyl guanidine followed by 250 mL of n-butanol and further heated to 93 ± 3 °C, maintained the same at 4 hrs with stirring. After completion of the reaction, reaction mixture was cooled to 75 ± 5 °C and was added 1750 mL of water and stirred at same temperature for 30 mins. Further, to the reaction mass was added 250 mL of glacial acetic acid; stirred and cooled to Room temperature (RT). The resulting solid was filtered and washed with 500 mL of water followed by washing with methanol and dried to yield titled compound.
Dry weight: 290- 330 gm.

Example 2:

Preparation of 4-(4-Amino-6-chloropyrimidin-2-ylamino)benzonitrile (III):

[0030] 1900 ml of phosphorus oxychloride was added to a reaction vessel, to this was added 190 g of 4-(4-Amino-6-hydroxypyrimidin-2-ylamino)benzonitrile under stirring at RT. The reaction mass was slowly heated to 80- 85 °C and maintained at same temperature for 16- 18 hr. After completion of the reaction, phosphorous oxychloride was distilled off and stripped with 950 ml of ethyl acetate and slowly added 1900 ml of chilled water and adjusted pH of the reaction mass to 9- 10 with 950 ml of 50% aqueous potassium carbonate. The solid was filtered and dried under vacuum at 55- 60 °C overnight.

Example 3:

Preparation of 4-(4-Amino-6-chloropyrimidin-2-ylamino)benzonitrile (III):

[0031] 1500 ml of phosphorus oxychloride and 300 g of 4-(4-Amino-6-hydroxypyrimidin-2-ylamino) benzonitrile at 27 ± 3 °C were added to the reaction vessel and heated to 97 ± 3 °C; and maintained at same temperature for 7 hrs. After completion of the reaction, ∼50% of phosphorous oxychloride was distilled off under vacuum at 83 ± 2 °C and the reaction mixture was cooled to 30 ± 5 °C. In a clean RB flask were added 1000 g of ice and 1000 mL of water and was slowly added the above obtained reaction mass. The pH of the reaction mass was adjusted to 9.0 ± 0.5 with 50% potassium carbonate solution in water at 5 ± 5 °C. The reaction mixture was stirred; filtered and the obtained solid was washed with 600 mL of water and suck dried. The wet solid was charged in to a RB flask at 27 ± 3 °C and was added 600 mL of water. The resulting wet solid was taken into a RB flask and was added 600 mL of water, stirred; and filtered. The obtained solid was washed with water and suck dried. 3000 mL of ethyl acetate was charged into a RB flask and to this was added the obtained solid and heated to 43 ± 3 °C. The reaction mass was stirred for 20 mins and filtered hot. The residue was washed with ethyl acetate and collected filtrate (1) at 27 ± 3 °C. The obtained solid was again taken in RB flask and was added 1500 mL of ethyl acetate and heated to 43 ± 3 °C; stirred and filtered hot reaction mass and collected filtrate (2). Both filtrates (1) and (2) were taken and distilled off solvent at 47 ± 3 °C. To the residue was added 900 mL of heptane and cooled to 27 ± 3 °C and was again added 1100 mL of heptane; stirred; filtered the solid and suck dried, and the solid was washed with heptane. The obtained solid was dried under vacuum. To the obtained 190 g of crude was added 380 mL of dimethyl formamide and 20.4 mL of 1,8-Diazabicycloundec-7-ene under stirring at 27 ± 3 °C and heated the reaction mass to 47 ± 3 °C. To the obtained clear solution was added 760 ml of water and stirred for 1 hr. The reaction mass was cooled and filtered. The solid was washed with 760 mL of water twice and suck dried. The solid was washed with 48 mL of chilled methanol and the solid is suck dried. The obtained solid was further dried under vacuum to yield title compound.
Dry weight: 150- 180gm.

Example 4: Preparation of N-[6-Chloro-2-(4-cyanophenylamino)pyrimidin-4-yl]benzamide (IV)

[0032] 1400 ml of N-methyl pyrrolidine and 140 g of 4-(4-Amino-6-chloropyrimidin-2-ylamino)benzonitrile was charged into a reaction vessel. To this was added 85.49 g of dimethylamino pyridine and 87.21g of diazabicyclo undecene and stirred for 30 mins. To the reaction mixture was added 27.36 g of benzoyl chloride and stirred at RT for 30mins and heated to 80- 85 °C and maintained the same for 4 hrs. After completion of the reaction, the reaction mass was cooled to RT and was added 1400 ml of water followed by 1400 ml of 50% carbonate solution. Reaction mass was extracted with 1400 ml of dichloromethane and the dichloromethane layer was washed with 700 ml of water. The organic layers were separated and dried over of anhydrous sodium sulfate and filtered; distilled off dichloromethane and the solid was isolated.

Example 5: Preparation of N-[6-Chloro-2-(4-cyanophenylamino)pyrimidin-4-yl] benzamide (IV)

[0033] 3000 ml of acetonitrile; 150 g of 4-(4-Amino-6-chloropyrimidin-2-ylamino) benzonitrile and 187 g of Dimethylaminopyridine were added into a reaction vessel at 27 ± 3 °C and heated to 63 ± 2 °C under stirring. To the reaction mixture was added 425 mL of benzoyl chloride and heated to 78 ± 3 °C and maintained the same for 7 hrs. 50% of acetonitrile was distilled off from the reaction mixture and cooled to 63 ± 2 °C; To the reaction mixture was added 1500 mL of water; stirred for 15 mins at same temperature and filtered. The obtained product solid was washed with water and suck dried. The wet cake was taken into RB flask and was added 1500 mL of methanol, stirred and filtered. The obtained solid was washed with 150 mL of methanol and dried under vacuum.
Dry weight: 165-175 gm.

Example 6: Preparation of N-[5-Bromo-6-chloro-2-(4-cyanophenylamino)-pyrimidin-4-yl]-benzamide (V)

[0034] 1000 ml of dichloromethane and 100 g of N-[6-Chloro-2-(4-cyanophenylamino)pyrimidin-4-yl]benzamide was added to a reaction vessel. To this was added 76.5 g of N-Bromosuccinamide and 2.2 g (10M%) of ammonium acetate and stirred fro 4 hrs. After completion of the reaction, pH was adjusted to 10- 11 with 5% of aqueous sodium hydroxide solution (10 g in 200ml water). The reaction mass was filtered and the wet cake was slurried in 1000 ml of hot water at 55- 60 °C for 1hr and filtered. The obtained solid was dried under vacuum (0.5 kg/ cm²) at 55- 60 °C overnight.
Practical yield= 100 g.

Example 7: Preparation of N-[5-Bromo-6-chloro-2-(4-cyanophenylamino)-pyrimidin-4-yl]-benzamide (V)

[0035] 1500 ml of dichloromethane and 150 g of N-[6-Chloro-2-(4-cyanophenylamino)pyrimidin-4-yl]benzamide were added to a reaction vessel and to this was added 750 mL of acetic acid and 44.2 mL of liquid bromine solution at 27 ± 3 °C and stirred for 11 hrs. after completion of the reaction, to the reaction mixture was added 375 mL of water under stirring and maintained for 45 mins. To the reaction mixture was further added metabisulphate solution (60 g in 375 mL of water) and stirred further for 30 mins. The solid was filtered and washed with 300 mL of water and suck dried. The wet cake and 1500 mL of were charged into clean RB and adjusted pH 9.0 ± 0.5 with 50% potassium carbonate solution. The reaction mass was stirred and filtered; the solid was washed with 150 mL of water followed by 150 mL of dichloromethane. The obtained solid was dried under vacuum at 73 ± 2 °C to yield title compound.
Dry weight: 140- 165gm.

Example 8: Preparation of N-[5-Bromo-6-(4-cyano-2,6-dimethylphenoxy)-2-(4-cyano-phenylamino)pyrimidin-4-yl]-benzamide (VI)

[0036] 1000 ml of Dimethylformamide, 51.52 g of 3,5-Dimethyl-4-hydroxybenzonitrile, 106.9 g of Diazabicyclo undecene was added to a reaction vessel and stirred at RT. The reaction mixture was maintained at same temperature for 1 hr and added 100 g of N-[5-Bromo-6-chloro-2-(4-cyanophenylamino)-pyrimidin-4-yl]benzamide and continued stirring for 30 mins. The reaction mixture was heated to 100- 110 °C and further maintained at same temperature for 24 hr. After completion of the reaction, reaction mixture was cooled to RT and added 2000 ml of water and stirred at RT for 1hr. The reaction mixture was filtered. The obtained solid was dried under vacuum (0.5 kg/ cm²) at 55- 60°C overnight.

Example 9: Preparation of N-[5-Bromo-6-(4-cyano-2,6-dimethylphenoxy)-2-(4-cyano-phenylamino)pyrimidin-4-yl]-benzamide (VI):

[0037] 1300 ml of Dimethylformamide was added to a RB flask, to this was added 54 g of 3,5-dimethyl-4-hydroxybenzonitrile, 51.38 g of dimethyl amino pyridine, 68.30 g of diazabicyclo undecene and 150 g of N-[5-Bromo-6-chloro-2-(4-cyanophenylamino)-pyrimidin-4-yl]-benzamide at 27 ± 3 °C. The reaction mixture was heated to 73 ± 2 °C and maintained the same for 5 hrs. The reaction mixture was cooled to 27 ± 3 °C and filtered. The filtrate was taken into RB flask and was added 300 mL of IPA and stirred for 30 mins.

[0038] 3000 mL of water was taken in another RB flask and was added reaction mass. The reaction mass was heated to 47 ± 3 °C, stirred, cooled to 42 ± 3 °C and filtered hot. The solid was washed with water and suck dried at 27 ± 3 °C. The solid was further washed with 150mL of IPA and the wet cake was charged into clean RB flask. To this was added 1500 mL of dimethyl formamide and heated to 47 ± 3 °C. To the reaction mass was slowly added 3000 mL of water and continued stirring followed by cooling reaction mass to 27 ± 3 °C. Filtered the reaction mass, the solid was washed with water followed by IPA. The solid dried under vacuum to yield title compound.
Dry weight: 130- 170gm.

Example 10: Preparation of Etravirine

[0039] 400 ml of iso-propyl alcohol and 50 g of N-[5-Bromo-6-(4-cyano-2,6-dimethylphenoxy)-2-(4-cyano-phenylamino)-pyrimidin-4-yl]-benzamide was added to a reaction vessel and stirred at RT. Separately, prepared sodium hydroxide solution, i.e. sodium hydroxide 12.5g solution in water 100ml was added to the reaction mixture and stirred at RT for 30mins and heated to 70- 75 °C. The reaction mixture was maintained at same temperature for 5hrs. After completion of the reaction, reaction mixture was cooled to RT, filtered. The solid obtained was dried under Vacuum at 55- 60 °C overnight.

Purification:

[0040] 600 ml of acetone was added to a reaction vessel, to this was added the above obtained solid (1eq) and heated to reflux and the same was maintained for 1 hr. Then the reaction mixture cooled to RT, and distilled out acetone under reduced pressure till 250 ml of acetone remained. Reaction mixture cooled to RT and filtered. The solid obtained was dried under vacuum (0.5 kg/ cm²) at 55- 60 °C for 5hr.
Practical yield= 24g.

Example 11: Preparation of Etravirine

[0041] 1350 mL of Acetonitrile taken into a RB flask at 27 ± 3 °C, to this was added 900 mL of IPA. To the reaction mixture 150 g of N-[5-Bromo-6-(4-cyano-2,6-dimethylphenoxy)-2-(4-cyano-phenylamino)pyrimidin-4-yl]-benzamide and 35.2 g of Lithium hydroxide monohydrate were added and heated to 59 ± 3 °C. The reaction mixture was maintained at same temperature for 10 hrs. After completion of the reaction, the reaction mixture cooled to 47 ± 3 °C and filtered. The solid was washed with acetonitrile and suck dried. The wet cake was taken into another flask and was added 1500 mL of water, stirred for 30 mins and filtered to obtain the solid. The solid was washed with water and dried under vacuum at 73 ± 3 °C to isolate Etravirine.
Dry weight: 70- 75g.

Purification of Etravirine:

[0042] 1000 Ml of acetone and 100 g of crude Etravirine were added to RB flask at 27 ± 3 °C and heated to 53 ± 3 °C. The reaction maintained at same temperature to form clear solution. The hot solution is filtered through celite and washed with 200 mL of hot acetone. The acetone was distilled off under vacuum till 200 mL remains in the reaction mixture and cooled to 27 ± 3 °C. 1500 mL of water was added to the reaction mixture, stirred and filtered. The solid was washed with water and dried under vacuum.
Dry weight: 90- 93g.

Claims

1. A process for preparing 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile (Etravirine) comprising the steps of:

a) condensing a compound of formula (V)

wherein L is a leaving group and P is an amino protecting group, with 3,5-dimethyl-4-hydroxybenzonitrile, and

b) deprotecting the compound of formula (VI)

wherein P is a suitable amino protecting group.

2. The process according to claim 1, wherein the condensation of step a) is carried out in the presence of a base and a solvent.

3. The process according to claim 2, wherein the base is selected from triethylamine, diisopropylethylamine, 1,8-diazabicyclo-[5,4.0]-undec-7-ene (OBU), 1,5-diazabicyclo-[4.3.0]-non-5-ene (DBN), 1,4-diazabicyclo-[2.2.2]-octane (DABCO), pyridine and 4-(dimethylamino)pyridine (DMAP) or mixtures thereof.

4. The process according to claim 2, wherein the solvent is selected from 1,4-dioxane, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide.

5. A process for preparing a compound of formula (V) comprising the steps of:

a) converting the -OH group of the compound of formula (II)

into a leaving group yielding a compound of formula (III),

b) protecting the compound of formula (III) to obtain a compound of formula (IV), and

c) brominating the compound of formula (IV)

to obtain a compound of formula (V),
wherein L is a leaving group and P is a suitable amino protecting group.

6. The process according to claim 5, wherein the leaving group in the compound of formula (III) is chloro.

7. The process according to claim 6, wherein the compound of formula (III) is prepared by treating the compound of formula (II) with a chlorinating agent selected from chlorine, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride and thionyl chloride.

8. The process according to claim 5, wherein the amino protecting group is selected from carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl, tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP),Tosyl (Ts) and other sulfonamides (such as Nosyl and Nps); preferably benzoyl group.

9. The process according to claim 8, wherein the protection of the compound of formula (III) is carried out by treating the compound of formula (III) with benzoyl chloride in the presence of a base in a suitable organic solvent.

10. The process according to claim 5, wherein the bromination of the compound of formula (IV) is carried out by a treatment with bromine in the presence of an acid.

11. The process according to claim 5, wherein the compound of formula (II) is prepared by condensing ethyl cyanoacetate with N-cyanophenyl guanidine; optionally, in the presence of a base in a solvent; preferably the base is potassium-tert-butoxide and the solvent is n-butanol.

12. The process according to claim 5, wherein the compound of formula (V) is further converted into Etravirine.

13. A process for preparing Etravirine according to claims 1 and 5 comprising the steps of:

a) condensing ethyl cyanoacetate with N-cyanophenylguanidine to get a compound of formula (II),

b) converting the -OH group of the compound of formula (II) into a leaving group yielding a compound of formula

c) protecting the amino group of the compound of formula (III) to get a compound of formula (IV),

d) brominating the compound of formula (IV) to get a compound of formula (V),

e) condensing the compound of formula (V) with 3,5-dimethyl-4-hydroxybenzonitrile to get a compound of formula (VI), and

f) deprotecting the compound of formula (VI) to get Etravirine.

14. A compound of formula (II)

a compound of formula (III)

wherein L is a leaving group is selected from chloro, bromo, tosylates and mesylates;
a compound of formula (IV)

wherein L is a leaving group is selected from chloro, bromo, tosylates and mesylates and P is a suitable amine protecting group is selected from carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl, tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP),Tosyl (Ts) and other sulfonamides (such as Nosyl and Nps);
a compound of formula (V),

wherein L is a leaving group is selected from chloro, bromo, tosylates and mesylates and P is a suitable amine protecting group is selected from carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl, tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP),Tosyl (Ts) and other sulfonamides (such as Nosyl and Nps); or
a compound of formula (VI).

wherein P is a suitable amine protecting group is selected from carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl, tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP),Tosyl (Ts) and other sulfonamides (such as Nosyl and Nps).

15. The use of any of the compounds of claim 14 in the preparation of Etravirine.

Ansprüche

1. Verfahren zur Herstellung von 4-[[6-Amino-5-brom-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitril (Etravirin), umfassend die folgenden Schritte:

a) Kondensieren einer Verbindung der Formel (V)

wobei L eine Abgangsgruppe ist und P eine Aminoschutzgruppe ist, mit 3,5-Dimethyl-4-hydroxybenzonitril und

b) Entschützen der Verbindung der Formel (VI)

wobei P eine geeignete Aminoschutzgruppe ist.

2. Verfahren nach Anspruch 1, wobei die Kondensation aus Schritt a) in Gegenwart einer Base und eines Lösungsmittels ausgeführt wird.

3. Verfahren nach Anspruch 2, wobei die Base ausgewählt ist aus Triethylamin, Diisopropylethylamin, 1,8-Diazabicyclo-[5.4.0]-undec-7-en (DBU), 1,5-Diazabicyclo-[4.3.0]-non-5-en (DBN), 1,4-Diazabicyclo-[2.2.2]-octan (DABCO), Pyridin und 4-(Dimethylamino)pyridin (DMAP) oder Gemischen davon.

4. Verfahren nach Anspruch 2, wobei das Lösungsmittel ausgewählt ist aus 1,4-Dioxan, Tetrahydrofuran, Aceton, Acetonitril, N,N-Dimethylformamid oder Dimethylsulfoxid.

5. Verfahren zur Herstellung einer Verbindung der Formel (V), umfassend die folgenden Schritte:

a) Umwandeln der -OH-Gruppe der Verbindung der Formel (II)

in eine Abgangsgruppe, wodurch eine Verbindung der Formel (III)

hervorgebracht wird,

b) Schützen der Verbindung der Formel (III), um eine Verbindung der Formel (IV)

zu erhalten und

c) Bromieren der Verbindung der Formel (IV)

um eine Verbindung der Formel (V) zu erhalten,
wobei L eine Abgangsgruppe ist und P eine geeignete Aminoschutzgruppe ist.

6. Verfahren nach Anspruch 5, wobei die Abgangsgruppe in der Verbindung der Formel (III) Chlor ist.

7. Verfahren nach Anspruch 6, wobei die Verbindung der Formel (III) hergestellt wird, indem die Verbindung der Formel (II) mit einem Chlorierungsmittel behandelt wird, ausgewählt aus Chlor, Phosphoroxychlorid, Phosphorpentachlorid, Phosphortrichlorid und Thionylchlorid.

8. Verfahren nach Anspruch 5, wobei die Aminoschutzgruppe ausgewählt ist aus Carbobenzyloxy (Cbz), p-Methoxybenzylcarbonyl, tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl (Bn), Carbamatgruppe, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-Methoxyphenyl (PMP), Tosyl (Ts) und anderen Sulfonamiden (wie etwa Nosyl und Nps); vorzugsweise Benzoylgruppe.

9. Verfahren nach Anspruch 8, wobei die Schützung der Verbindung der Formel (III) ausgeführt wird, indem die Verbindung der Formel (III) in Gegenwart einer Base in einem geeigneten organischen Lösungsmittel mit Benzoylchlorid behandelt wird.

10. Verfahren nach Anspruch 5, wobei die Bromierung der Verbindung der Formel (IV) durch eine Behandlung mit Brom in Gegenwart einer Säure ausgeführt wird.

11. Verfahren nach Anspruch 5, wobei die Verbindung der Formel (II) durch Kondensieren von Ethylcyanoacetat mit N-Cyanophenylguanidin hergestellt wird; gegebenenfalls in Gegenwart einer Base in einem Lösungsmittel; vorzugsweise ist die Base Kalium-tert-butoxid und das Lösungsmittel ist n-Butanol.

12. Verfahren nach Anspruch 5, wobei die Verbindung der Formel (V) ferner zu Etravirin umgewandelt wird.

13. Verfahren zur Herstellung von Etravirin nach den Ansprüchen 1 und 5, umfassend die folgenden Schritte:

a) Kondensieren von Ethylcyanoacetat mit N-Cyanophenylguanidin, um eine Verbindung der Formel (II)

zu erhalten,

b) Umwandeln der -OH-Gruppe der Verbindung der Formel (II) in eine Abgangsgruppe, wodurch eine Verbindung der Formel



hervorgebracht wird,

c) Schützen der Aminogruppe der Verbindung der Formel (III), um eine Verbindung der Formel (IV)

zu erhalten,

d) Bromieren der Verbindung der Formel (IV), um eine Verbindung der Formel (V)

zu erhalten,

e) Kondensieren der Verbindung der Formel (V) mit 3,5-Dimethyl-4-hydroxybenzonitril, um eine Verbindung der Formel (VI)

zu erhalten und

f) Entschützen der Verbindung der Formel (VI), um Etravirin zu erhalten.

14. Verbindung der Formel (II)

Verbindung der Formel (III)

wobei L eine Abgangsgruppe ist, ausgewählt aus Chlor, Brom, Tosylaten und Mesylaten; Verbindung der Formel (IV)

wobei L eine Abgangsgruppe ist, ausgewählt aus Chlor, Brom, Tosylaten und Mesylaten und P eine geeignete Aminschutzgruppe ist, ausgewählt aus Carbobenzyloxy (Cbz), p-Methoxybenzylcarbonyl, tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl (Bn), Carbamatgruppe, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-Methoxyphenyl (PMP), Tosyl (Ts) und anderen Sulfonamiden (wie etwa Nosyl und Nps);
Verbindung der Formel (V)

wobei L eine Abgangsgruppe ist, ausgewählt aus Chlor, Brom, Tosylaten und Mesylaten und P eine geeignete Aminschutzgruppe ist, ausgewählt aus Carbobenzyloxy (Cbz), p-Methoxybenzylcarbonyl, tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl (Bn), Carbamatgruppe, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-Methoxyphenyl (PMP), Tosyl (Ts) und anderen Sulfonamiden (wie etwa Nosyl und Nps); oder
Verbindung der Formel (VI)

wobei P eine geeignete Aminschutzgruppe ist, ausgewählt aus Carbobenzyloxy (Cbz), p-Methoxybenzylcarbonyl, tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl (Bn), Carbamatgruppe, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-Methoxyphenyl (PMP), Tosyl (Ts) und anderen Sulfonamiden (wie etwa Nosyl und Nps).

15. Verwendung beliebiger der Verbindungen nach Anspruch 14 bei der Herstellung von Etravirin.

Revendications

1. Procédé de préparation du 4-[[6-amino-5-bromo-2-[(4-cyanophényl)amino]-4-pyrimidinyl]oxy]-3,5-diméthylbenzonitrile (étravirine) comprenant les étapes de :

a) condensation d'un composé de formule (V)

dans laquelle L représente un groupe partant et P représente un groupe de protection amino, avec du 3,5-diméthyl-4-hydroxybenzonitrile, et

b) déprotection du composé de formule (VI)

dans laquelle P représente un groupe de protection amino approprié.

2. Procédé selon la revendication 1, dans lequel la condensation de l'étape a) est effectuée en présence d'une base et d'un solvant.

3. Procédé selon la revendication 2, dans lequel la base est choisie parmi la triéthylamine, la diisopropyléthylamine, le 1,8-diazabicyclo-[5.4.0]-undéc-7-ène (OBU), le 1,5-diazabicyclo-[4.3.0]-non-5-ène (DBN), le 1,4-diazabicyclo-[2.2.2]-octane (DABCO), la pyridine et la 4-(diméthylamino)pyridine (DMAP) ou des mélanges de ceux-ci.

4. Procédé selon la revendication 2, dans lequel le solvant est choisi parmi le 1,4-dioxane, le tétrahydrofurane, l'acétone, l'acétonitrile, le N,N-diméthylformamide ou le sulfoxyde de diméthyle.

5. Procédé de préparation d'un composé de formule (V) comprenant les étapes de :

a) conversion du groupe -OH du composé de formule (II)

dans un groupe partant produisant un composé de formule (III),

b) protection du composé de formule (III) pour obtenir un composé de formule (IV), et

c) bromation du composé de formule (IV)

pour obtenir un composé de formule (V),
dans laquelle L représente un groupe partant et P représente un groupe de protection amino approprié.

6. Procédé selon la revendication 5, dans lequel le groupe partant dans le composé de formule (III) est un groupe chloro.

7. Procédé selon la revendication 6, dans lequel le composé de formule (III) est préparé par traitement du composé de formule (II) avec un agent de chloration choisi parmi le chlore, l'oxychlorure de phosphore, le pentachlorure de phosphore, le trichlorure de phosphore et le chlorure de thionyle.

8. Procédé selon la revendication 5, dans lequel le groupe de protection amino est choisi parmi un groupe carbobenzyloxy (Cbz), p-méthoxybenzylcarbonyle, tert-butyloxycarbonyle (BOC), 9-fluorénylméthyloxycarbonyle (FMOC), acétyle (Ac), benzoyle (Bz), benzyle (Bn), un groupe carbamate, p-méthoxybenzyle (PMB), 3,4-diméthoxybenzyle (DMPM), p-méthoxyphényle (PMP), tosyle (Ts) et d'autres groupes sulfonamide (tels qu'un groupe nosyle et Nps) ; de préférence un groupe benzoyle.

9. Procédé selon la revendication 8, dans lequel la protection du composé de formule (III) est effectuée par traitement du composé de formule (III) avec du chlorure de benzoyle en présence d'une base dans un solvant organique approprié.

10. Procédé selon la revendication 5, dans lequel la bromation du composé de formule (IV) est effectuée par traitement au brome en présence d'un acide.

11. Procédé selon la revendication 5, dans lequel le composé de formule (II) est préparé par condensation de cyanoacétate d'éthyle avec de la N-cyanophénylguanidine ; éventuellement, en présence d'une base dans un solvant ; de préférence la base est le tert-butoxyde de potassium et le solvant est le n-butanol.

12. Procédé selon la revendication 5, dans lequel le composé de formule (V) est en outre converti en étravirine.

13. Procédé de préparation d'étravirine selon les revendications 1 à 5, comprenant les étapes de :

a) condensation de cyanoacétate d'éthyle avec de la N-cyanophénylguanidine pour obtenir un composé de formule (II),

b) conversion du groupe -OH du composé de formule (II) en un groupe partant produisant un composé de formule

dans laquelle L représente un groupe partant

c) protection du groupe amino du composé de formule (III) pour obtenir un composé de formule (IV),

dans laquelle L représente un groupe partant et P représente un groupe de protection

d) bromation du composé de formule (IV) pour obtenir un composé de formule (V),

e) condensation du composé de formule (V) avec du 3,5-diméthyl-4-hydroxybenzonitrile pour obtenir un composé de formule (VI), et

f) déprotection du composé de formule (VI) pour obtenir de l'étravirine.

14. Composé de formule (II),

composé de formule (III)

dans laquelle L représente un groupe partant choisi parmi un groupe chloro, un groupe bromo, des groupes tosylate et des groupes mésylate ;
composé de formule (IV)

dans laquelle L représente un groupe partant choisi parmi un groupe chloro, un groupe bromo, des groupes tosylate et des groupes mésylate et P représente un groupe de protection amine approprié choisi parmi un groupe carbobenzyloxy (Cbz), p-méthoxybenzylcarbonyle, tert-butyloxycarbonyle (BOC), 9-fluorénylméthyloxycarbonyle (FMOC), acétyle (Ac), benzoyle (Bz), benzyle (Bn), un groupe carbamate, p-méthoxybenzyle (PMB), 3,4-diméthoxybenzyle (DMPM), p-méthoxyphényle (PMP), tosyle (Ts) et d'autres groupes sulfonamide (tels qu'un groupe nosyle et Nps) ;
composé de formule (V)

dans laquelle L représente un groupe partant choisi parmi un groupe chloro, un groupe bromo, des groupes tosylate et des groupes mésylate et P représente un groupe de protection amine approprié choisi parmi un groupe carbobenzyloxy (Cbz), p-méthoxybenzylcarbonyle, tert-butyloxycarbonyle (BOC), 9-fluorénylméthyloxycarbonyle (FMOC), acétyle (Ac), benzoyle (Bz), benzyle (Bn), un groupe carbamate, p-méthoxybenzyle (PMB), 3,4-diméthoxybenzyle (DMPM), p-méthoxyphényle (PMP), tosyle (Ts) et d'autres groupes sulfonamide (tels qu'un groupe nosyle et Nps) ; ou
composé de formule (VI)

dans laquelle P représente un groupe de protection amine approprié choisi parmi un groupe carbobenzyloxy (Cbz), p-méthoxybenzylcarbonyle, tert-butyloxycarbonyle (BOC), 9-fluorénylméthyloxycarbonyle (FMOC), acétyle (Ac), benzoyle (Bz), benzyle (Bn), un groupe carbamate, p-méthoxybenzyle (PMB), 3,4-diméthoxybenzyle (DMPM), p-méthoxyphényle (PMP), tosyle (Ts) et d'autres groupes sulfonamide (tels qu'un groupe nosyle et Nps).

15. Utilisation de l'un quelconque des composés selon la revendication 14 dans la préparation d'étravirine.